It is generally accepted that the amino acid sequence of a protein determines its ultimate three-dimensional structure. In the hierarchic view, the primary structure determines regular repeating secondary structures, which in turn fold up into a tertiary structure. Researchers have noted the certain amino acids have a preference for a given secondary structure, and a number of schemes have been developed that use amino acid preferences to predict secondary structure from primary structure. If the amino acid preferences were absolute, then the protein folding problem would undoubtedly be solved. Since the preferences are not absolute, one can view the protein folding problem in reverse and ask the question: Why is each amino acid found in every type of secondary structure? If this question can be answered, we might be well on our way to solving the protein folding problem, and our first two specific aims deal with this question. 1. We propose to investigate exceptional sequences of amino acids that are predicted to be in one secondary structure from amino acid preferences, that are found in another secondary structure. These are the interesting sequences because they are the demonstrated failures of our prediction methods. Our working hypothesis is that the environment is important in determining the secondary structure formed by an amino acid sequence. We would synthesize exceptional sequences and follow the secondary structure as a function of solvent system. 2. We propose to investigate the hypothesis that a few amino acids nucleate the formation of a secondary structure, and that continuation of the structure is relatively independent of the amino acids until continuation of the structure is broken. Sequences that readily form an alpha-helix or beta-strand in solution are well known; can we induce indifferent amino acids to continue this structure? 3. We propose to use circular dichroism to investigate the secondary structure of proteins of current interest, and to improve our system of analyzing CD for secondary structure. This continues our longstanding interest in relating the spectra of proteins to their secondary structure, but with considerably reduced emphasis.